PPARα alleviates iron overload‐induced ferroptosis in mouse liver. (15th June 2022)

• Record Type: Journal Article
• Authors: Xing, Guowei; Meng, Lihua; Cao, Shiyao; Liu, Shenghui; Wu, Jiayan; Li, Qian; Huang, Wendong; Zhang, Lisheng
• Is Part Of: EMBO reports. Volume 23:Number 8(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-06-15
• Subjects: Ferroptosis -- Gpx4 -- Liver -- PPARα -- TRF; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202052280
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: Ferroptosis is an iron‐dependent form of non‐apoptotic cell death implicated in liver, brain, kidney, and heart pathology. How ferroptosis is regulated remains poorly understood. Here, we show that PPARα suppresses ferroptosis by promoting the expression of glutathione peroxidase 4 (Gpx4) and by inhibiting the expression of the plasma iron carrier TRF. PPARα directly induces Gpx4 expression by binding to a PPRE element within intron 3. PPARα knockout mice develop more severe iron accumulation and ferroptosis in the liver when fed a high‐iron diet than wild‐type mice. Ferrous iron (Fe 2+ ) triggers ferroptosis via Fenton reactions and ROS accumulation. We further find that a rhodamine‐based "turn‐on" fluorescent probe(probe1) is suitable for the in vivo detection of Fe 2+ . Probe1 displays high selectivity towards Fe 2+, and exhibits a stable response for Fe 2+ with a concentration of 20 μM in tissue. Our data thus show that PPARα activation alleviates iron overload‐induced ferroptosis in mouse livers through Gpx4 and TRF, suggesting that PPARα may be a promising therapeutic target for drug discovery in ferroptosis‐related tissue injuries. Moreover, we identified a fluorescent probe that specifically labels ferrous ions and can be used to monitor Fe 2+ in vivo . Synopsis: Gpx4 and TRF are PPARα target genes involved in ferroptosis regulation. Loss of PPARα aggravates iron overload‐induced ferroptosis in vivo, while activation of PPARα is sufficient to largely alleviate iron overload‐induced liver damage. PPARα activation alleviates iron overload‐induced ferroptosis in mouse livers through Gpx4 and TRF. Activated PPARα and ferrostatin‐1 similarly protect against ferroptosis‐induced liver injury. PPARα deficiency influences iron metabolism in the liver. Abstract : Gpx4 and TRF are PPARα target genes involved in ferroptosis regulation. Loss of PPARα aggravates iron overload‐induced ferroptosis in vivo, while activation of PPARα is sufficient to largely alleviate iron overload‐induced liver damage.